Clinical Impact of New Treatment Strategies for HER2-Positive Metastatic Breast Cancer Patients with Resistance to Classical Anti-HER Therapies

Abstract

HER2-positive breast cancer accounts for 15–20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients due to primary or acquired treatment resistance, and metastasis remains an incurable disease. This article reviews the main mechanisms underlying resistance to anti-HER2 treatments, focusing on newer HER2-targeted therapies. The progress in anti-HER2 drugs includes the development of novel antibody–drug conjugates with improvements in the conjugation process and novel linkers and payloads. Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. The combination of anti-HER2 agents with other drugs is also being evaluated. The addition of immunotherapy checkpoint inhibitors shows some benefit in a subset of patients, indicating the need for useful biomarkers to properly stratify patients. Besides, CDK4/6 and tyrosine kinase inhibitors are also included in the design of new treatment strategies. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms.

A bibliometric analysis of HER2-positive breast cancer: 1987–2024

“…The centrality of Goel et al.’s article, “Overcoming therapeutic resistance in HER2-positive breast cancers with CD4/6 inhibitors”, in citation analysis affirms this focus ( 20 ). Several mechanisms of treatment resistance are recognized including activation of the PI3K/Akt/mTOR signaling pathway in response to prolonged treatment course, which may cause resistance through expression of mutated PTEN or PIK3CA genes ( 21 ). Detailed understanding of this pathway, gained through scientific exploration, has led to the FDA approval of capisertib, an Akt inhibitor ( 22 ).…”

“…This exemplifies the importance of cohesive international efforts to elucidate the interaction between signaling pathways, tumor proliferation, and treatment response at a molecular level to identify druggable targets that improve patient outcomes. Other important mechanisms of resistance backed by numerous publications include Src mutations, MET mutations, and HER2 activating mutations ( 21 ).…”

Targeting Interleukin-13 Receptor α2 and EphA2 in Aggressive Breast Cancer Subtypes with Special References to Chimeric Antigen Receptor T-Cell Therapy

“…Despite the availability of therapeutic alternatives, these subtypes are associated with the most adverse prognoses. Even with the implementation of adjuvant therapies, including chemotherapy and trastuzumab, around 20% of patients with Her-2-enriched BCA experience metastasis and recurrence [55]. Recent therapeutic advancements, such as tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs), and novel monoclonal antibodies (mAbs), have been introduced for the aggressive treatment of Her-2/neu-positive patients.…”

Trastuzumab Biosimilar (HLX02), Pertuzumab Plus Chemotherapy in Patients with HER2-Positive Metastatic Breast Cancer after Progression of Trastuzumab: A Prospective, Phase II Study

“…However, not all people can afford ADCs due to expensive cost, and patients who used ADCs will also eventually experience disease progression. Up to now, there is no standard of care for third-line or later treatment [3][4][5].…”